title: Are therapeutic effects of antiacne agents mediated by activation of FoxO1 and inhibition of mTORC1?
abstract: Acne pathogenesis has recently been linked to decreased nuclear FoxO1 levels and increased mTORC1 activity. This hypothesis postulates that antiacne agents either enhance nuclear FoxO activity or inhibit mTORC1. Benzoyl peroxide (BPO), by activation of oxidative stress-inducible kinases, increases nuclear FoxO levels promoting Sestrin3-mediated AMPK activation. Furthermore, BPO-derived ROS may activate AMPK via ataxia-telangiectasia mutated. Isotretinoin and all-trans retinoic acid may stimulate FoxO gene expression. Doxycycline may enhance FoxOs nuclear retention by inhibiting the expression of exportin 1. Suppression of TNFα signalling by tetracyclines, erythromycin and other macrolides may attenuate IKKβ-TSC1-mediated mTORC1 activation. Erythromycin attenuates ERK1/2 activity and thereby increases TSC2. Azelaic acid may decrease mTORC1 by inhibiting mitochondrial respiration, increasing cellular ROS and nuclear FoxO levels. Antiandrogens may attenuate mTORC1 by suppressing mTORC2-mediated Akt/TSC2 signalling. This hypothesis unmasks a common mode of action of antiacne agents as either FoxO enhancers or mTORC1 inhibitors and thus provides a rational approach for the development of new antiacne agents.
authors.forename: Bodo C
authors.initials: BC
authors.lastname: Melnik
authors.forename: Gerd
authors.initials: G
authors.lastname: Schmitz
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000152:Acne Vulgaris / Q000188:drug therapy*; D001585:Benzoyl Peroxide / Q000494:pharmacology; D003879:Dermatologic Agents / Q000737:chemistry*; D003998:Dicarboxylic Acids / Q000494:pharmacology; D004789:Enzyme Activation; D004917:Erythromycin / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D015474:Isotretinoin / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018384:Oxidative Stress; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013752:Tetracycline / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D003879:Dermatologic Agents; D003998:Dicarboxylic Acids; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D046912:Multiprotein Complexes; D004917:Erythromycin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D015474:Isotretinoin; C010038:azelaic acid; D013752:Tetracycline; D001585:Benzoyl Peroxide